Premium
TrkB Agonist Treatment in Old Age Does Not Mitigate Diaphragm Neuromuscular Dysfunction and Sarcopenia
Author(s) -
Vasdev Amrit Kaur,
Greising Sarah M.,
Sieck Gary C,
Mantilla Carlos B
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1295.3
Subject(s) - sarcopenia , tropomyosin receptor kinase b , neuromuscular transmission , medicine , neuromuscular junction , diaphragm (acoustics) , endocrinology , repetitive nerve stimulation , muscle atrophy , atrophy , denervation , agonist , stimulation , neurotrophic factors , biology , receptor , neuroscience , myasthenia gravis , physics , acoustics , loudspeaker
Neurotrophic signaling is essential to the maintenance of diaphragm muscle function across the lifespan. With aging, there is an age‐related loss of neurotrophic signaling and a resultant increase in diaphragm muscle denervation and impairment in neuromuscular transmission. We hypothesized that enhancing neurotrophic signaling via the tropomyosin‐related kinase receptor subtype B (TrkB) using the small molecule TrkB agonist 7,8‐dihydroxyflavone (7,8‐DHF) would mitigate age‐related changes in diaphragm neuromuscular transmission and possibly sarcopenia (muscle atrophy and force loss). Adult male TrkB F616A mice (n=32) were randomized to receive 6‐month oral treatment with vehicle (control), 7,8‐DHF, or co‐treatment with 7,8‐DHF and 1NMPP1(a specific inhibitor of TrkB kinase activity in TrkB F616A mice) beginning at 18 and ending at 24 months of age. Mice were analyzed for neuromuscular transmission failure using diaphragm muscle‐phrenic nerve preparations, diaphragm muscle force, and morphologic characteristics of sarcopenia. Chronic 7,8‐DHF treatment did not improve diaphragm neuromuscular function or force (P≥0.25). Co‐treatment with 7,8‐DHF and 1NMPP1 decreased the ratio of the initial nerve stimulation‐derived to initial muscle stimulation‐derived force (~22%) compared to vehicle (p=0.01), consistent with a deleterious effect of inhibiting TrkB kinase activity on aging diaphragm muscle. With age, there was fiber type specific atrophy of type IIa and type IIx and/or IIb diaphragm muscle fibers. There was no evidence of a protective effect of 7,8‐DHF on muscle fiber cross‐sectional area. Taken together, these results support a role for BDNF/TrkB signaling in old age but do not support 7,8‐DHF as a therapeutic agent to mitigate age‐related effects on diaphragm muscle function. Support or Funding Information Supported by R01‐AG044615, T32‐HL105355, and the Mayo Clinic.